Colistin is amphipathic, cannot be absorbed from the gastrointestinal tract and is administered intramuscularly, intravenously (IV) or via inhalation. In the case of pneumonia, aerosolized route of administration is favorable as it presumably delivers a high concentration of drug directly to the infection site. Colistimethate sodium is an FDA approved drug, however, its aerosolized use represents a new method of administration not currently FDA-approved in the United States. In this proposal, the inactive prodrug colistimethate sodium has been selected to use for aerosolization as it is better tolerated than colistin sulphate. It is a randomized, open-labeled Phase 1 trial of aerosolized and/or IV formulations of colistin as multiple doses over seven days.

A Phase 1, Open-Labeled Study of the Safety, Tolerability and Pharmacokinetics of Aerosolized Colistimethate Sodium After Multiple Doses Administered Separately or in Combination With Intravenous Colistimethate Sodium in Healthy Adults

(N=12) subjects in Dosing period 1 receive 3.3mg/kg colistin base activity IV every 8 hours, total of 21 doses, followed by a washout period of at least 3 days. In Dosing period 2, subjects receive 75mg colistin base activity every 6 hours via aerosol, for a total of 28 doses, followed by a washout period. In Dosing period 3, subjects receive combination IV and aerosolized doses: IV: 3.3mg/kg colistin base activity IV every 8 hours, total of 21 doses, Aerosol: 75mg colistin base activity every 6 hours via aerosol, total of 28 doses.

"Colistin" (also known as polymyxin E) is one of at least 13 derivatives of the inactive prodrug colistin methanesulfonate). It is amphipathic, cannot be absorbed from the gastrointestinal tract and is administered intramuscularly, intravenously (IV) or via inhalation. While approved for aerosolized use in the United Kingdom, and used in Europe for decades as such, aerosolized colistin is not FDA-approved in the United States. The intravenous formulation is approved for use in the U.S., but due to the age of the drug, it did not undergo rigorous studies of safety prior to FDA-approval. Thus, detailed pharmacokinetic data are limited and dosing is not standardized, although the maximum IV dose should not exceed 5mg/kg/day, divided into two to four equal doses. In the United Kingdom, the recommended dosing of nebulized colistin for adults is one million units (1MIU) twice daily. Despite the paucity of dosing and safety guidelines, aerosolized colistin is being prescribed regularly out of necessity given the emergence of multi-drug resistant organisms (MDROs). MDROs are strongly associated with nosocomial pneumonia and several strains are only susceptible to this older drug, thus there is an urgent need for clarification on the safe use of colistin, including in aerosolized form as this delivers a high concentration of drug directly to the infection site. It is a randomized, open-labeled Phase 1 trial of aerosolized and/or IV formulations of colistin as multiple doses over seven days.

Eligibility

Ages Eligible for Study:

18 Years to 45 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

Informed consent obtained and signed

Aged between 18 and 45 years, inclusive

Body Mass Index (BMI, weight in kg divided by the square of height in meters) between 18 and 35.0 kg/m^2, inclusive

Able to comply with protocol requirements for the entire duration of the study

Heterosexually active females of child-bearing potential, defined as being physiologically capable of becoming pregnant, unless they agree to use two of the following acceptable methods of contraception throughout their participation in the study and for at least 12 weeks after the final dose: (a) established use of oral, injected or implanted hormonal contraception, (b) intrauterine Device (IUD or Coil) (c) a female barrier method (diaphragm or cervical/vault cap) and/or (d) condom plus spermicidal cream/gel

Heterosexually active males unless they agree to use two concomitant acceptable methods of contraception throughout their participation in the study and for at least 12 weeks after receiving their final dose of study medication (examples include: vasectomy combined with latex condom with spermicide, latex condom with spermicide combined with a female partner who practices an acceptable method of contraception as indicated above)

History or current abuse of alcohol, barbiturates, amphetamines, tetrahydrocanninol, phencyclidine, cocaine, heroin, or other narcotics, as evidenced by a reported history or positive screen for these agents

Any clinically significant (as deemed by the Principal Investigator) history of asthma; cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (including eating disorders), endocrine, metabolic, immunologic, dermatologic, neurologic (including a history of seizures, ataxia, or Myastenia Gravis), psychological, or psychiatric disease; and/or a past or family history of porphyria

Use of tobacco/nicotine within 3 months prior to Screening and for the entire duration of the study);

Treatment with another investigational drug 60 days prior to and/or during the study

Co-enrollment in another study involving the intake of medication

Immunocompromised status, including a positive HIV-1 (Human Immunodeficiency Virus) or HIV-2 test by ELISA at screening

Previously demonstrated clinically significant allergy or hypersensitivity to colistimethate sodium or its excipients

Donation of blood or significant blood loss within 56 days of study Enrollment or during study duration, or plasma donation within 28 days preceding study Enrollment

Proteinuria (spot urine) greater than trace and/or hematuria greater than trace; Note: Subjects may undergo a repeat screening test of out-of-range analyte(s) at the discretion of the investigator to confirm a plausible alternative explanation that will be indicated in the source documentation. A repeat laboratory test may be used to satisfy eligibility requirements.

Intake of any of the following medications within 30 days prior to Screening and during the study: acyclovir, adefovir, aminoglycosides, amphotericin, cisplatin, cyclosporine, fluoroquinolones, foscarnet, ganciclovir, pamidronate, sirolimus, tacrolimus, and vancomycin, and/or any neuromuscular blockers;- Intake of NSAIDs (ibuprofen, naproxen, etodolac) within 48 hours of dosing and any inhaled medication within 5 days of dosing. Additionally, subjects may be excluded due to intake of medications not listed here at the discretion of the PIs (Principal Investigators)

Intake of NSAIDs (ibuprofen, naproxen, etodolac) within 48 hours of dosing and any inhaled medication within 5 days of dosing. Additionally, subjects may be excluded due to intake of medications not listed here at the discretion of the PIs;

FEV1 (Forced Expiratory Volume) <80 percent predicted

Prior evidence (symptoms within the past year) of vestibular problems or neuropathy

Abnormal QT interval at screening ECG (Electrocardiogram) (Bazett correction >450 milliseconds) or significant abnormities according to the cardiologist's final reading

A grade 3 or 4 clinical or confirmed laboratory toxicity (as outlined in Appendix C) which does not return to grade 2 or lower;

Any condition that would, in the opinion of the investigator, place the subject at an unacceptable risk or injury, or render the subject unable to meet the requirements of the protocol.

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01863719